Hydrochloric Acid → Diethylamine

Participants

Reaction Conditions

Reaction Steps

To a solution of (+/−)-methyl 6-(cyclopentyl(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)methylamino)nicotinate (972 mg, 2.13 mmol) in THF (10 mL) was added 2N aqueous LiOH (10.7 mL, 21.4 mmol). The mixture was stirred at 50° C. overnight. The mixture was neutralized by addition of 1N aqueous HCl and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in DMF (5 mL). HATU (1.19 g, 3.15 mmol) was added. The mixture was stirred for 45 min. Methyl 3-aminopropanoate hydrochloride (435 mg, 3.15 mmol) and N,N-diisopropylethylamine (1.08 g, 8.4 mmol) were added. The resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with aqueous NH4Cl. The organic layer was washed with water, dried over Na2SO4, and concentrated under reduced pressure to give crude (+/−)-methyl 3-(6-(cyclopentyl(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)methylamino)nicotinamido)propanoate (1.2 g). Resolution by SFC (Column: AD 250 mm*20 mm*5 μm, Mobile phase: 45:55 CO2:methanol, Flow rate: 80 mL/min, Modifier: 0.1% diethylamine) to give methyl 3-(6-(cyclopentyl(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)methylamino)nicotinamido)propanoate, Isomer 1 (Retention time 1.36 min, 450 mg) and methyl 3-(6-(cyclopentyl(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)methylamino)nicotinamido)propanoate, Isomer 2 (Retention time 3.50 min, 460 mg).

Provenance & Evidence